The studies in this proposal are designed to determine if slight, presymptomatic lesions of the brain dopaminergic and/or serotonergic neurons can be assessed (i.e. unmasked) through the use of sensitive behavioral paradigms combined with drug challenge. Long-Evans rats will be used as subjects and they will be treated with the systemically administered neurotoxins 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine. By varying the dose of these toxins, the magnitude of the lesion can be varied. The lesion magnitude for the dopaminergic system will range from 0% (i.e. control) to a maximum 75% depletion. These dopaminergic lesions will be accompanied by serotonergic lesions (simultaneously induced by both toxins) ranging in magnitude from 0% up to approximately 60% depletion. Both of these toxins have proven invaluable in advancing our understanding of the factors which lead to the degeneration of central dopaminergic and serotonergic neurons and, as such, have served as excellent models of Parkinson's disease. However, the use of rodents to explore these models has been somewhat restricted by the failure to demonstrate behavioral deficits associated with the toxin-induced damage. In this regard, however, the PI has obtained some degree of success stemming from use of carefully chosen behavioral paradigms used in conjunction with drug challenge tests. The demonstration that rodents with MPTP or methamphetamine-induced dopaminergic lesions do exhibit behavioral deficits has provided support for the validity of these models.